Soft β-drenegic blocking agents

ABSTRACT

New soft β-adrenergic blocking agents, useful in the treatment or prevention of cardiovascular disorders and in the treatment of glaucoma, have the formula ##STR1## wherein n is an integer from 0 to 10; R is C 6  -C 12  cycloalkyl-C p  H 2p  --, C 6  -C 18  polycycloalkyl-C p  H 2p  --, C 6  -C 18  polycycloalkenyl-C p  H 2p  -- or C 6  -C 12  cycloalkenyl-C p  H 2p  -- (wherein p is 0, 1, 2 or 3), or together with the adjacent ##STR2## group represents a variety of other complex ester groupings; R 1  is C 1  -C 7  alkyl; and Ar is a divalent radical containing at least one aromatic nucleus. The corresponding pharmaceutically acceptable acid addition salts are also described.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a division of application Ser. No. 08/239,414, filedMay 6, 1994, now U.S. Pat. No. 5,482,961 which is a division ofapplication Ser. No. 07/997,248, filed Dec. 28, 1992, now U.S. Pat. No.5,334,601; which is a division of application Ser. No. 07/822,127, filedJan. 17, 1992, now U.S. Pat. No. 5,202,347; which is a division ofapplication Ser. No. 07/692,260, filed Apr. 26, 1991, now U.S. Pat. No.5,135,926; which is a continuation of application Ser. No. 06/286,879,filed Dec. 20, 1988, now abandoned; which is a division of applicationSer. No. 06/922,462, filed Oct. 23, 1986, now U.S. Pat. No. 4,829,086;which is a continuation of application Ser. No. 06/741,846, filed asPCT/US85/00322, Feb. 28, 1985, now abandoned; which is acontinuation-in-part of my earlier application Ser. No. 589,359, filedMar. 14, 1984, now abandoned incorporated by reference herein in itsentirety and relied upon.

FIELD OF THE INVENTION

The present invention provides novel compounds containing at least onearomatic nucleus which are soft β-adrenergic blocking agents, useful inthe treatment or prevention of cardiovascular disorders and in thetreatment of glaucoma.

BACKGROUND OF THE INVENTION

Many β-adrenergic blocking agents are known and used; unfortunately,however, these agents are generally subject to facile oxidativemetabolic degradations. Many of the metabolites also possess significantβ-blocking activity and, due to their different pharmacokineticproperties, make dosing and optimization of therapy difficult. Themetabolites of bufuralol, for example, have longer biological half-livesthan the parent drug. Francis et al, Biomed. Mass, Spectrometry,3,281-285 (1976). Consequently, it is difficult to determine an adequatedose of the known β-blockers for administration, especially whenadministering them therapeutically to patients suffering from anginapectoris, hypertension or unexpected arrhythmias during surgicaloperations. It would be most desirable to design β-blockers which wouldbe metabolized in a simple, predictable and controllable manner in onestep to an inactive metabolite, regardless of the conditions of thepatient and other drugs used. This would necessitate, however, avoidingoxidative metabolism.

The present inventor has previously devised a general soft drug approachhaving such objectives, one specific aspect of that approach being theinactive metabolite method. Bodor, in Proceedings of the 2ndIUPAC-IUPHAR Symposium on Strategy in Drug Research, Noordwijkerhout, J.A. Keverling Buisman (ed.), Elsevier Scientific Publishing Company,Amsterdam, 1982; Bodor, Belgian Patent No. 889,563, Nov. 3, 1981; Chem.Abstr. 97:6651n (1982). The principles of the inactive metaboliteapproach are:

(1) Start the design process with a known inactive metabolite of a drug.

(2) Alter the metabolite to obtain a structure that resembles (isostericand/or isoelectronic) the starting or an analogous drug.

(3) Design the structure and metabolism of the new soft compound in sucha way as to yield the starting inactive metabolite in one step withoutgoing through toxic intermediates.

(4) Control transport and binding properties as well as the rate ofmetabolism and pharmacokinetics by molecular manipulations in theactivation stage.

However, it is not necessary to wait for an inactive metabolite to beisolated; it may be possible to design the inactive metabolite duringthe general drug design process based on knowledge of structuralrequirements for activity as well as elimination and enzymatic cleavage.

Recently, several patent publications have described various series ofshort acting β-adrenergic blocking compounds containing ester moietieswhich are structurally related to some of the compounds of the presentinvention. Thus, Matier U.S. Pat. No. 4,454,154, issued Jun. 12, 1984,describes a method of treating glaucoma by topical administration ofselected β-blockers. Lower alkyl (C₁ -C₁₀) and lower cycloalkyl (C₃ -C₅)esters are among the compounds generically disclosed by Matier, but onlyalkyl esters are specifically described. See also related Erhardt et alU.S. Pat. No. 4,387,103, issued Jun. 7, 1983 and American HospitalSupply Corportion's corresponding International Application No.PCT/US81/01514 published under International Publication No. W082/01869on Jun. 10, 1982; again, lower alkyl and lower cycloalkyl esters aregenerically disclosed, but of these only the lower alkyl esters arespecifically described. The Erhardt et al patent and its PCT counterpartprovide a method for the treatment or prophylaxis of cardiac disorders.A related series of short acting β-blockers is described in AktiebolagetHassle's European Patent Application No. 81850095.1, published on Dec.9, 1981 under European Publication No. 0041491. The Hassle applicationgenerically discloses lower alkyl (C₁ -C₇) and lower cycloalkyl (C₃ -C₆)esters, among others, but again does not specifically describe anycycloalkyl esters. Moreover, none of these publications appear toaddress the problem addressed by the present invention, i.e. how todesign β-blockers which would be metabolized in one simple, predictable,controllable step to an inactive metabolite which avoiding oxidativemetabolism; moreover, the esters of the publications are generally lesscomplex structurally than those described hereinbelow. See also Erhardtet al, J. Med, Chem., 25, 1408-1412 (1982). Similar simple alkyl esterswere described much earlier, e.g. Barrett et al U.S. Pat. No. 3,663,607,issued May 16, 1972.

SUMMARY AND OBJECTS OF THE INVENTION

In view of the foregoing, it is an object of this invention to provide anew class of β-adrenergic agents which will be metabolized in a simple,predictable and controllable manner in one step to an inactivemetabolite. It is another object of the present invention to provide newβ-adrenergic agents which are not subject to significant oxidativemetabolism. It is another object of this invention to apply the presentinventor's general inactive metabolite approach to the design of novelsoft β-blockers.

These and other objects of the present invention are achieved byproviding compounds of the formula ##STR3## wherein:

n is an integer from 0 to 10 inclusive;

R is (1) C₆ -C₁₂ cycloalkyl-C_(p) H_(2p) -- wherein p is 0, 1, 2 or 3;(2) C₆ -C₁₈ polycycloalkyl-C_(p) H_(2p) -- wherein p is defined asabove; (3) C₆ -C₁₈ polycycloalkenyl-C_(p) H_(2p) -- wherein p is definedas above; (4) C₆ -C₁₂ cycloalkenyl-C_(p) H_(2p) wherein p is defined asabove; (5) --CH₂ --X--R₂ wherein X is S, SO or SO₂ and R₂ is C₁ -C₇alkyl or C₃ -C₁₂ cycloalkyl, ##STR4## wherein R₂ is defined as above;##STR5## wherein X is defined as above, and wherein R₃ is C₁ -C₇ alkyland R₄ is C₁ -C₇ alkyl or wherein R₃ and R₄ taken together represent--(CH₂)_(m) -- wherein m is 3 or 4 and --(CH₂)_(m) -- is optionallysubstituted by one to three C₁ -C₇ alkyl; ##STR6## wherein R₅ ishydrogen or C₁ -C₇ alkyl and R₆ is unsubstituted or substituted C₁ -C₇alkyl, C₃ -C₁₂ cycloalkyl, C₃ -C₁₂ cycloalkenyl or C₂ -C₈ alkenyl, thesubstituents being selected from the group consisting of halo, C₁ -C₇alkoxy, C₁ -C₇ alkylthio, C₁ -C₇ alkylsulfinyl, C₁ -C₇ alkylsulfonyl,##STR7## alkyl), or R₆ is unsubstituted or substituted phenyl or benzyl,the substituents being selected from the group consisting of C₁ -C₇alkyl, C₁ -C₇ alkoxy, halo, carbamoyl, C₂ -C₈ alkoxycarbonyl, C₂ -C₈alkanoyloxy, C₁ -C₇ haloalkyl, mono(C₁ -C₇ alkyl)amino, di(C₁ -C₇alkyl)amino, mono(C₁ -C₇ alkyl)carbamoyl, di(C₁ -C₇ alkyl(carbamoyl, C₁-C₇ alkylthio, C₁ -C₇ alkylsulfinyl and C₁ -C₇ alkylsulfonyl; ##STR8##wherein R₅ and R₆ are defined as above; or ##STR9## wherein R₅ isdefined as above, and R₇ and R₈, which can be the same or different, areeach hydrogen, C₁ -C₇ alkyl, C₃ -C₁₂ cycloalkyl, phenyl or benzyl, or R₇and R₈ are combined such that --NR₇ R₈ represents the residue of asaturated monocyclic secondary amine;

R₁ is C₁ -C₇ alkyl;

and Ar is a divalent radical containing at least one aromatic nucleus.

The compounds of the present invention avoid the disadvantages of manyknown β-blockers resulting from their active metabolites. The compoundsof formula (I) are rationally designed so that when administered to amammal they are subjected to an enzymatic hydrolytic (i.e. esterase)process which is much faster than oxidative metabolism and which leadsto hydrolyzed metabolites which possess very little or no β-adrenergicactivity. Thus, for example, in the case of a group of preferredmetoprolol derivatives of the invention, such are designed tohydrolytically deactivate to the phenylacetic acid derivative, i.e. thecompound of the formula ##STR10## which is an inactive metabolite ofmetoprolol and the major metabolite found in the urine. [See, forexample, Borg et al, Acta Pharmacol. Toxicol., 36 (Suppl. V), 125-135(1975).] The rate of hydrolysis deactivation may be controlled by thestructure of the esters.

Accordingly, the compounds of the present Invention exhibit excellentβ-blocking efficacy without adverse side effects for a certain duration,dependent only on the hydrolytic metabolism rate. As a consequence, itis easy to control and maintain adequate therapeutic action with adesirable onset time using the present compounds. The onset time isusually short compared with conventional β-adrenergic blocking agents;therefore, the instant compounds are expected to be of particular use inthe treatment of arrhythmias, ischemic heart disease and hypertension,possibly attending surgical operations. The instant compounds are alsoexpected to be of special value when used in the treatment of glaucoma,since they will not only reduce intraocular pressure when appliedlocally to the eye, but because of their "soft" nature will deactivateduring absorption and thus avoid the typical β-blocker systemic sideeffects which attend use of known β-blockers for this purpose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph plotting the mean change in heart rate (beats/minute)with time following subcutaneous administration of 25 g/kg ofisoproterenol to groups of rats pretreated 60 minutes prior toisoproterenol administration with 6 mg/kg of test compound or controlvehicle;

FIG. 2 is a graph plotting the mean change in heart rate response(beats/minute) with time in groups of rats pretreated with controlvehicle or with test compound at 15, 60 or 90 minutes prior toadministration of isoproterenol (25 μg/kg s.i.) at time zero;

FIG. 3 is a graph plotting the mean change in blood pressure response(mm Hg) with time following subcutaneous administration of 25 μg/kg ofisoproterenol to groups of rats pretreated 60 minutes prior toisoproterenol administration with 6 mg/kg of test compound or controlvehicle; and

FIG. 4 is a graph plotting the β-adrenergic blocking activities ofselected test compounds on the heart rate of dogs.

DETAILED DESCRIPTION OF THE INVENTION

With respect to the various groups encompassed by the generic terms usedin this specification, the following definitions and explanations areapplicable:

The divalent radicals containing at least one aromatic nucleus which arerepresented by Ar can be unsubstituted or substituted monocyclic orpolycyclic ring systems and may include hetero ring atoms, particularlyN and O. Illustrative divalent radicals represented by Ar include thefollowing:

(1) phenylene, i.e. a radical of the formula ##STR11## especially1,4-phenylene and 1,3-phenylene, optionally bearing one or moresubstituents such as C₁ -C₇ alkyl, e.g. CH₃ CH₂ -- or CH₃ --; C₁ -C₇alkyl--O--C₁ -C₇ alkylene--, e.g. CH₃ OCH₂ CH₂ --; C₂ -C₈ alkenyl, e.g.CH₂ ═CH--CH₂ --; C₁ -C₇ alkyl--S--, e.g. CH₃ --S--; C₂ -C₈ alkenyl--O--,e.g. CH₂ CH═CH₂ --O--; C₃ -C₁₂ cycloalkyl, e.g. cyclopentyl; C₁ -C₇alkyl--CONH--, e.g. CH₃ CH₂ CH₂ CONH-- or CH₃ CONH--; C₁ -C₇ alkyl--CO--, e.g. CH₃ CO--; and/or H₂ NCO--C₁ -C₇ alkylene--; e.g. H₂NCO--CH₂ --;

(2) divalent fused ring systems containing two or three rings,optionally containing one or two N, S or O ring atoms, such as:##STR12## and

(3) divalent aryl-alkylene-aryl systems, e.g. phenylene-C₁ -C₃alkylene-phenyl radicals such ##STR13## Preferably, the divalent radicalrepresented by Ar is selected such that the ##STR14## grouping informula (I) either simply replaces a hydrogen atom on the correspondingring of a known β-blocker or replaces a non-critical ring substituent onthe corresponding ring of a known β-blocker, e.g. a lower alkyl, loweralkyl--O-- lower alkylene--, lower alkyl --CONH-- or H₂ NCO--loweralkylene-- substituent. Particularly preferred compounds of theinvention bear such a structural relationship to metoprolol, bufuralol,alprenolol, bunolol, xipranolol, nadolol, tiprenolol, oxprenolol,penbutolol, pindolol, carteolol, propranolol, acebutolol, atenolol andpractolol. Analogues of metoprolol are especially preferred. It shouldbe emphasized that the divalent radicals represented by Ar must containat least one true aromatic nucleus, i.e. at least one benzene ring.Thus, a ring system such as ##STR15## is not within the meaning of An asdefined herein. Hereto atoms may be present, however, when located In aring or rings fused or appended to a benzene ring, e.g. as in (2) (a),(d) and (e) above.

The alkyl, alkenyl and alkylene groupings encompassed by any of thestructural variables in formula (I) can be straight or branched-chaingroups containing the indicated number of carbon atoms. The term "lower"used in conjunction with such radicals indicates that they may containup to 7 carbon atoms.

Specific examples of alkyl radicals encompassed by formula (I), whetheras specific values for R₁ or as a portion of an R or Ar group, includemethyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl and theirbranched-chain isomers, e.g. isopropyl, isobutyl and tert-butyl.Preferred values for R₁ are isopropyl and tert-butyl.

The alkenyl radicals encompassed by various R and Ar values can beexemplified by vinyl, propenyl and butenyl and the branched-chain groupshaving 3 or more carbon atoms.

The alkylene moieties encompassed by C_(n) H_(2n) (when n is other thanzero) as well as those encompassed by various values for R and Ar aretypified by methylene, ethylene, trimethylene, 2-methyltrimethylene,2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene,ethylmethylene, tetramethylene, pentamethylene, hexamethylene and thelike.

The alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl,alkanoyloxy, monoalkylamino, dialkylamino, monoalkylcarbamoyl anddialkylcarbamoyl groupings are of the type ##STR16## respectively,wherein alkyl is as hereinbefore defined and exemplified.

The halo substituents can be chloro, bromo, iodo or fluoro. Thehaloalkyl substituents can be monohaloalkyl or polyhaloalkyl, straightor branched-chain, substituted with from 1 to 3 halogen atoms, the term"halogen" as used herein including chlorine, bromine, iodine orfluorine. Specific examples of the contemplated monohaloalkyl andpolyhaloalkyl groups include chloromethyl, dichloromethyl,trtchloromethyl, bromomethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, 1-chloroethyl, 2-chloroethyl,2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 1,2-dichloroethyl,1-chloropropyl, 3-chloropropyl, 1-chlorobutyl, 1-chloropentyl,2-chlorohexyl, 4-chlorobutyl and the like.

When R in formula (I) is C₆ -C₁₂ cycloalkyl--C_(p) H_(2p) --, thecycloalkyl groups contain 6 to 8 ring atoms and may optionally bear oneor more, preferably one to four, alkyl substituents, Exemplary suchcycloalkyl groups are cyclohexyl, 2,6-dimethylcyclohexyl,3,3,5,5-tetramethylcyclohexyl, 2-methylcyclohexyl, 2-ethylcyclohexyl,4-propylcyclohexyl, 5-butylcyclohexyl, 2,3-dimethylcyclohexyl,2,4-dimethylcyclohexyl, 2,5dimethylcyclohexyl,2,3,4-trimethylcyclohexyl, 2,3-dimethyl-5-ethylcyclohexyl,2,5-dimethyl-6-propylcyclohexyl, 2,4-dimethyl-3-butylcyclohexyl,2,2,4,4-tetramethylcyclohexyl, 3,3,6,6-tetramethylcyclohexyl,3,3,4,5,5-pentamethylcyclohexyl, 3,3,4,5,5,6-hexamethylcyclohexyl,3,3,5-trimethyl-4-ethylcyclohexyl, 3,4,4-trimethyl-5-propylcyclohexyl,cycloheptyl, 3-methylcycloheptyl, 5-propylcycloheptyl, 6-butylcloheptyl,7-methylcycloheptyl, cyclooctyl, 2-methylcyclooctyl, 3-ethylcyclooctyl,3,3,4-trimethylcyclooctyl, 3,3,5,5-tetramethylcyclooctyl and the like.Among the presently preferred cycloalkyl--C_(p) H_(2p) -- groupsrepresented by R are cyclohexyl, 2,6-dimethylcyclohexyl and3,3,5,5-tetramethylcyclohexyl. Thus, when R is cycloalkyl--C_(p) H_(2p)--, p is preferably zero or one, most preferably zero. Even morepreferred are cycloalkyl--C_(p) H_(2p) -- groups containing at leasteight carbon atoms in the cycloalkyl portion. Most especially preferredare cycloalkyl--C_(p) H_(2p) -- groups wherein the cycloalkyl portioncontains 6 to 8 ring atoms and bears at least two alkyl substituents onthe ring (e.g. 2,6-dimethylcyclohexyl and3,3,5,5-tetramethylcyclohexyl).

When a cycloalkyl radical is present in formula (1) as a portion of Aror as a different portion of R (e.g. when R is --CH₂ --X--R₂ wherein R₂is C₃ -C₁₂ cycloalkyl), then such a cycloalkyl radical can contain 3 to8 ring atoms and may optinally bear one or more, preferably one to four,alkyl substituents. Examples of such cycloalkyl groups include theexamples of C₆ -C₁₂ cycloalkyl radicals recited above as well as thelower homologues, e.g. cyclopropyl, 2-methylcyclopropyl,3-ethylcyclopropyl, 2-butylcyclopropyl, 3-pentylcyclopropyl,2-hexylcyclopropyl, cyclobutyl, 2-methylcyclobutyl,2,3-dimethylcyclobutyl, 3-butylcyclobutyl, 4-hexylcyclobutyl,2,3,3-trimethylcyclobutyl, 3,3,4,4-tetramethylcyclobutyl, cyclopentyl,2-methylcyclopentyl, 3-ethylcyclopentyl, 4-butylcyclopentyl,methylcyclopentyl, 3-pentylcyclopentyl, 4-hexylcyclopentyl,2,3-dimethylcyclopentyl, 2,2,5,5-tetramethylcyclopentyl,2,3,4-trimethylcyclopentyl, 2,4-dimethyl-3-ethylcyclopentyl,2,2,3,4,4-pentamethylcyclopentyl, 2,3-dimethyl-3-propylcyclopentyl andthe like. When a cycloalkenyl radical is present in formula (I) as aportion of R, corresponding unsaturated radicals such as cyclopentenyland cyclohexenyl and the like, including alkyl-substituted cycloalkenylradicals, are contemplated (depending, of course, on the carbon atomlimitations in the generic definitions). Again, when R is C₆ -C₁₂cycloalkenyl--C_(p) H_(2p) --, p is preferably zero or one, mostpreferably zero. An exemplary C₆ -C₁₂ cycloalkenyl--C_(p) H_(2p) --grouping is 3,5,5-trimethyl-2-cyclohexen-1-yl.

The polycycloalkyl--C_(p) H_(2p) -- radicals represented by R arebridged or fused saturated alicyclic hydrocarbon systems consisting oftwo or more rings, optionally bearing one or m ore alkyl substituentsand having a total of 6 to 18 carbon atoms in the ring portion. Thecorresponding bridged or fused unsaturated alicyclic hydrocarbon systemsare intended by the term "C₆ -C₁₈ polycycloalkenyl--C_(p) H_(2p) --".Such polycycloalkyl and polycycloalkenyl radicals constitute especiallypreferred embodiments of this invention, most especially the bridgedentities. These polycyclic groups represented by R are exemplified byadamantyl (especially 1- or 2- adamantyl), adamantylmethyl (especially1-adamantylmethyl), adamantylethyl (especially 1-adamantylethyl),bornyl, norbornyl (e.g. exo-norbornyl or endonorbornyl), norbornenyl(e.g. 5-norbornen-2-yl), norbornylmethyl (e.g. 2-norbornylmethyl),norbornylethyl (e.g. 2-norbornylethyl), decahydronaphthyl (e.g. cis ortrans decahydronaphth-2-yl ),6,6-dimethylbicyclo[3.1.1]hept-2-en-2-ethyl,(+)-(3-methylnorborn-2-yl)methyl, 1,3,3-trimethyl -2-norbornyl and5-norbornene-2-methyl. Thus, in the case of polycyclic radicals, p ispreferably 0, 1 or 2.

When R in formula (I) is ##STR17## wherein --NR₇ R₈ represents theresidue of a saturated monocyclic secondary amine, such monocyclespreferably have 5 to 7 ring atoms optionally containing another heteroatom (--O--, --S-- or --N--) in addition to the indicated nitrogen atom,and optionally bear one or more substituents such as phenyl, benzyl andmethyl. Illustrative of residues of saturated monocyclic secondaryamines which are encompassed by the --NR₇ R₈ term are morpholino,1-pyrrolidinyl, 4-benzyl-1-piperazinyl, perhydro-1,2,4-oxathiazin-4-yl,1- or 4- piperazinyl, 4-methyl-1-piperazinyl, piperidino,hexamethyleneimino, 4-phenylpiperidino, 2-methyl-1-pyrazolidinyl, 1- or2-pyrazolidinyl, 3-methyl -1-imidazolidinyl, 1- or 3-imidazolidinyl,4-benzylpiperidino and 4-phenyl-1piperazinyl.

The compounds of formula (I) can be prepared by reacting a startingmaterial of the formula ##STR18## wherein, R, n and Ar are defined asabove and Z is ##STR19## wherein Hal is a halogen atom, especially Cl orBr, with a primary amine of the formula

    NH.sub.2 R.sub.1                                           (III)

wherein R₁ is defined as above. This process is preferably carried outin the presence of an inert solvent, although it can be carried out inthe absence of solvent. While time and temperature are not criticalfactors, the reaction is generally conducted at a temperature from aboutroom temperature to about 200° C. (preferably from about 60° to 120°C.), for a period of time from about 30 minutes to 24 hours. Suitableinert solvents include ethers such as dioxane, tetrahydrofuran andethylene glycol monomethyl ether; aromatic hydrocarbons such as benzene,toluene or xylene; lower alcohols such as methanol, ethanol andisopropanol; and esters such as ethyl acetate, dimethylformamide anddimethylsulfoxide. The process is frequently carried out in the presenceof a basic compound, for example an inorganic base such as sodiumcarbonate, sodium hydroxide, sodium bicarbonate, sodium amide or sodiumhydride; or an organic base such as triethylamine, tripropylamine,pyridine, quinoline, DBN (1,5-diazabiscyclo[4.3.0]non-5-ene), DBU(1,8-diazabicyclo[5.4.0]undec-7-ene) or Dabco(1,4-diazabicyclo[2.2.2.]octane or triethylenediamine). The ratio of theamounts of reactants used can be selected over a wide range. It is,however, generally desirable for the amine of formula (III) to be usedin an equimolar quantity or in an excess amount, preferably from anequimolar quantity to about seven times the molar quantity.

The starting materials of formula (II) can be conveniently prepared byreacting the corresponding compounds of the formula ##STR20## wherein R,n and Ar are defined as before, with an epihalogenohydrin of the formula##STR21## wherein Hal is a halogen atom, especially Cl or Br. Thisprocess can be carried out in the presence of a suitable basic compound,for example an inorganic base such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodium methoxide,sodium ethoxide, sodium hydride, sodium metal, potassium metal or sodiumamide, or an organic basic compound such as piperidine, pyridine,triethylamine, DBN, DBU or Dabco, in the presence or absence of asolvent. Suitable solvents are, for example, a lower alcohol such asmethanol, ethanol or isopropanol; a ketone such as acetone; an ethersuch as dioxane, tetrahydrofuran or ethylene glycol monomethyl ether; oran aromatic hydrocarbon such as benzene, toluene or xylene. In thisreaction, the epihalogenohydrin of formula (V) ordinarily can be used inan equimolar to excess quantity, preferably about 5 to 15 times themolar quantity of the formula (IV) starting material. The process can beconducted at a temperature between about 0° and 150° C., preferably atfrom about 50° to about 100° C. Usually, the reaction product is amixture of the corresponding (2,3-epoxy)propoxy and3-halogeno-2-hydroxypropoxy compounds encompassed by formula (II) andcan be used as such to prepare the formula (I) compounds.

The starting materials of formula (IV) can be prepared by esterificationof carboxylic acids of the formula

    HOOC--C.sub.n H.sub.2n --Ar--OH                            (VI)

wherein n and Ar are defined as before, or the corresponding acidchlorides or acid anhydrides, by reaction with an alochol of the formula

    ROH                                                        (VIII)

wherein R is defined as before. Reaction conditions, solvents and thelike vary with the particular reactants employed. Generally speaking,when an acid of formula (VI) is utilized as the starting material, theprocess is conducted in the presence of a conventional esterificationcatalyst, e.g. an inorganic acid such as hydrogen chloride gas,concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, borontrifluoride or hypochlorous acid, or an organic acid such astrifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonicacid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid,trifluoromethanesulfonic acid anhydride, thionyl chloride, acetonedimethyl acetal and the like. A cation exchange resin may also be usedas the catalyst. The reaction can be carried out In the presence orabsence of solvent, at a temperature between about -20° to about 200°C., preferably between about 0° and about 150° C., for a period of timefrom about 10 minutes to about 20 hours. If a solvent is employed, aninert solvent is desirable, for example, an aromatic hydrocarbon such asbenzene, toluene or xylene; a halogenated hydrocarbon such aschloroform, dichloromethane, dichloroethane or carbon tetrachloride; oran ether such as diethyl ether, tetrahydrofuran, dioxane or ethyleneglcol monomethyl ether. The ratio of amount of a compound of formula(VI) to an alcohol of the formula ROH is not subject to any specificrestriction and may be suitably selected from a wide range. Whileusually it is desirable that the latter is used in an excess quantity inthe absence of the solvent, in the presence of the solvent it isdesirable that the latter is used in an equimolar to 5 times the molarquantity of the former, more preferably an equimolar to 2 times themolar quantity of the former. This reaction can advantageously beeffected by using a drying agent such as anhydrous calcium chloride,anhydrous cupric sulfate, anhydrous calcium sulfate, phosphoruspentoxide or the like.

Alterntively, an acid of formula (VI) can be converted to thecorresponding salt of the type

    M.sup.+- OOC--C.sub.n H.sub.2n --Ar--OH                    (VIII)

where n and Ar are defined as before and M⁺ is Na⁺ or the like; thatsalt can then be reacted with a halide of the formula

    R--Hal                                                     (IX)

where R is defined as before and Hal is halogen, preferably Cl or Br, toafford the corresponding starting material of formula (IV).

The compounds of the invention which contain a sulfinyl (SO) or sulfonyl(SO₂) group can be prepared by oxidation of the correspondingsulfur-containing compounds of the invention. Thus, for example, acompound of formula (I) wherein R is --CH₂ --X--R₂ wherein X is S can betreated with one equivalent of m-chloroperbenzoic acid to afford thecorresponding sulfinyl derivative, while treatment of the thio compoundwith two equivalents of m-chloroperbenzoic acid yields the correspondingsulfonyl derivative. Thus, the compounds of formula (I) wherein Rcontains a sulfur atom, e.g. the compounds in which R is --CH₂ --X--R₂or ##STR22## wherein X is S and R₂, R₃ and R₄ are defined above, are ofvalue not only as soft β-adrenergic agents but also as chemicalintermediates to the corresponding soft drugs in which X is SO or SO₂.

The compounds of the present invention can also be prepared byesterification of the corresponding acid of the formula ##STR23##wherein n, Ar and R₁ are defined as above, under conditions similar tothe esterification of a compound of formula (VI ) as described above.

Equivalent to the compounds of formula (I) for the purposes of thisinvention are the corresponding acid addition salts formed withpharmaceutically acceptable acids. Illustrative of such acids areinorganic acids such as hydrochloric acid, sulfuric acid, hydrobromicacid and the like; and organic acids such as acetic acid, oxalic acid,succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid,citric acid, malonic acid, methanesulfonic acid, benzoic acid and thelike.

The compounds prepared by the procedures detailed above can easily beisolated and purified by usual separation means, e.g. solventextraction, dilution, recrystallization, column chromatography orpreparative thin-layer chromatography.

The compounds of the present invention also includes their opticalisomers.

For therapeutic use, e.g. in the treatment of angina pectoris andarrhythmias, a compound of formula (I) or its salt can be convenientlyadministered in the form of a pharmaceutical composition containing theformula (I) compound or its salt and a pharmaceutically acceptablecarrier therefor. Suitable carriers vary with the desired form of thepharmaceutical composition and may include diluents or excipients suchas fillers, binders, wetting agents, disintegrators, surface-activeagents, lubricants and the like.

The compound of the invention or its salt may be formulated togetherwith the carrier into any desired unit dosage form. Typical unit dosageforms include tablets, pills, powders, solutions, suspensions,emulsions, granules, capsules, suppositories; injectable solutions andsuspensions are particularly preferred.

In the preparation of tablets, carriers which are widely used in thisfield can be employed, e.g. excipients such as lactose, sucrose, sodiumchloride, glucose solution, urea, starch, calcium carbonate, kaolin,crystalline cellulose and silicic acid; binding agents such as water,ethanol, propanol, simple syrup, glucose, starch solution, gelatinsolution, carboxymethyl cellulose, shellac, methyl cellulose, calciumphosphate and polyvinylpyrrolidone; disintegrators such as dried starch,sodium alginate, agar-agar powder, laminalia powder, sodium bicarbonate,calcium carbonate, Tweens, sodium lauryl sulfate, stearic acidmonoglyceride, starch and lactose; disintegration inhibitors such assucrose, stearin, coconut butter and hydrogenated oil; absorptionaccelerators such as quaternary ammonium bases and sodium laurylsulfate; wetting agents such glycerin and starch; adsorbing agents suchas starch, lactose, kaolin, bentonite and colloidal silicic acid; andlubricants such as purified talc, stearic acid salts, boric acid powder,Macrogol and solid polyethylene glycol.

In the preparations of pills, carriers which are known and widely usedin this field can also be used, for example, excipients such as glucose,lactose, starch, coconut buter, hydrogenated vegetable oils, kaolin andtalc; binders such as powdered gum arabic, powdered tragacanth, gelatinand ethanol; and disintegrators such as laminaria and agar-agar. In thecase of tablets, they can be further coated with the usual coatingmaterials to make sugar-coated tablets, gelatin film-coated tablets,tablets coated with enteric coatings, tablets coated with films ordouble-layered tablets and multi-layer tablets.

In order to form suppositories, carriers which are known and widely usedin this field can also be used, for example, polyethylene glycols,coconut butter, higher alcohols, esters of higher alochols, gelatin andsemisynthesized glycerides.

In order to prepare formulations suitable for injection, solutions andsuspensions are sterilized and are preferably isotonic to blood. Inmaking injectable preparations, carriers which are commonly used in thisfield can aso be used, for example, water, ethyl alcohol, propyleneglycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,polyoxyethylene sorbitol and sorbitate esters. In these instances,adequate amounts of sodium chloride, glucose or glycerin can be added tomake the preparations isotonic.

Furthermore, the usual dissolving agents, buffers, analgesic agents andpreservatives can be added, as well as coloring materials, perfumes,seasoning agents, sweetening agents and other medicines, to thepharmaceutical compositions, if necessary or if desired.

The amount of a compound of formula (I) or its acid addition salt to bepresent in the pharmaceutical composition, e.g. for use in treatment ofangina pectoris and arrhythmias, can suitably be selected from a widerange, but usually 1 to 70% by weight of the total composition ispreferable.

As to the route of administration, e.g. for angina pectoris, same willvary with the particular composition used. For example, tablets, pills,solutions, suspensions, emulsions, granules and capsules can beadministered orally; and injectable preparations can be administeredintravenously, either alone or mixed with injection transfusions such asglucose solutions and amino acid solutions. If necessary, the injectablepreparations can be administered separately, by the intramuscular,intracutaneous, subcutaneous or intraperitoneal route.

The dosage of the compounds of the present invention is selectedaccording to the usage, purpose and conditions of symptoms. For example,when these compounds are administered therapeutically to patientssuffering from angina pectoris, hypertension, or unexpected arrhythmiasduring surgical operation, usually 0.5-6.0 mg/kg of the compound ofgeneral formula (I) or its acid addition salt may be administered.

The present compounds also may be continuously administered at suitableintervals, including 30 minutes to 60 minutes.

The compounds of the present invention and their salts reduceintraocular pressure when applied topically/locally to the eye, thus areof particlar use in the treatment of patients with glaucoma or in thetreatment of other patients who require lowering of ocular pressure(such as patients with elevated intraocular pressure who may be at riskof developing glaucoma). The instant compounds and their salts can beconveniently administered for these purposes by formulating the selectedβ-blocker, in an effective intraocular pressure lowering amount,together with a non-toxic ophthalmically acceptable carrier therefor.Suitable carriers will be apparent to those skilled in the art ofophthalmic formulations. Obviously, the choice of suitable carriers willdepend on the exact nature of the particular dosage form desired, e.g.whether the β-blocker is to be formulated into an ophthalmic solution orsuspension (typically for use as eye drops), an ophthalmic ointment orcream or an ophthalmic gel. Preferred dosage forms are solutions, whichcontain a major amount of water in addition to the active Ingredient.Minor amounts of other ingredients such as pH adjusters (e.g. a basesuch as NaOH) emulsifiers or dispersing agents, buffering agents,preservatives, wetting agents and jelling agents (e.g. methylcellulose)may also be present. Host preferably, the ophthalmic composition is asterile, isotonic, buffered aqueous solution. Generally speaking, theophthalmic composition containing the instant β-blockers may be preparedand may contain the various inert ingredients or carriers as previouslydescribed in the patent or non-patent literature as being suitable forophthalmic compositions comprising known β-blockers such as timolol andlabetolol. The amount of the β-blocker of this invention which will bepresent in the ophthalmic composition will of course vary with theparticular β-blocker employed and the type of formulation selected.Generally speaking, the composition will contain 0.01 to 5% of acompound of formula (I), preferably 0.25 to 2.5%; in other words, eachmL of solution will contain 0.1 to 50 mg, preferably 2.5 to 25 mg, ofthe free base. The dose administered ophthalmically will be selectedaccording to the particular compound employed and the size and conditionof the patient, but in any event will be a quantity sufficient to causea significant reduction in intraocular pressure.

In order to further illustrate the present invention and the advantagesthereof, specific examples of compounds of formula (I) are given below,it being understood that these examples are intended only asillustrative and are not in any way limitative. Also exemplified beloware the preparation of selected starting materials and the preparationof structurally related esters which are not claimed herein (e.g. thelower alkyl esters whose syntheses are given in EXAMPLE 5 below andwhich are homologues of the ethyl ester specifically described byBarrett et al, U.S. Pat. No. 3,663,607, issued May 16, 1972).

In the examples to follow, all melting points are uncorrected and wereobtained by using electrothermal capillary melting point apparatus.

EXAMPLE 1

Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid (7.6 g),p-toluenesulfonic acid (1 g) and benzene (300 mL) were refluxed withcontinuous water separation for 8 hours. The mixture was cooled andwashed with a 10% Na₂ CO₃ solution, then with water. Drying over MgSO₄and evaporation of the solvent in vacuo gave 12.24 g of cyclohexyl4-hydroxyphenyl acetate. That compound can be represented by theformula: ##STR24##

EXAMPLE 2

A mixture of 2,6-dimethylcyclohexyl alcohol (11.4 g),4-hydroxyphenylacetic acid (9.12 g), p-toluenesulfonic acid (1 g) andbenzene (300 mL) was refluxed with continuous water separation for 20hours. The mixture was filtered and the filtrate was washed with a 10%Na₂ CO₃ solution, then with water. Drying over MgSO₄ and evaporation invacuo afforded 8.02 g of 2,6-dimethylcyclohexyl 4-hydroxyphenyl acetate.That product has the structural formula: ##STR25##

EXAMPLE 3

A mixture of 4-hydroxyphenylacetic acid (6.08 g),3,3,5,5-tetramethylcyclohexyl alcohol (6.24 g), p-toluenesulfonic acid(1 g) and benzene (300 mL) was refluxed for 8 hours with continuouswater separation. The mixture was cool ed and washed with Na₂ CO₃, thenwith water. Drying over MgSO₄ and evaporation in vacuo yielded 12.3 g of3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate. That product,which can be represented by the structural formula ##STR26## ischaracterized by the following NMR (CDCl₃, TMS, ppm): 7.00(d, J=BHz,2H), 6.60(d, J=8 Hz, 2H), 5.00(broad, 1H), 3.40(s, 2H) and 1.8-0.80(m,18H).

EXAMPLE 4

A mixture of ethyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate(29.5 g), 1N NaOH solution (200 mL), and ethanol (200 mL) was refluxedfor I hour, and then evaporated in vacuo. The residue was dissolved withwater (200 mL). The insoluble material was removed by filtration. To thefiltrate was added dilute hydrochloric acid, and the crystals werefiltered, washed with water, dried and recrystallized from water toyield 20 g of 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetic acid, ascolorless needles melting at 212°-213° C. That compound has thestructural formula: ##STR27##

EXAMPLE 5

A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), n-propanol(40 mL) and SOCl₂ (2 mL, 0.028 mol) was refluxed for 3 hours, thenevaporated in vacuo. The residue was extracted with ethyl acetate (200mL), washed with 10% Na₂ CO₃, then water dried (MgSO₄), and evaporatedin vacuo to give n-propyl 4-hydroxyphenylacetate as an oil. A solutionof n-propyl 4-hydroxyphenylacetate (5.8 g, 0.03 mol) in epichlorohydrin(50 mL) was refluxed in the presence of DBU (2 mL, 0.014 mol) for 2hours. After the excess epichlorohydrin was removed, the residue wasrefluxed with isopropylamine (20 mL, 0.23 mol) in n-propanol (50 mL),for 4 hours, then was evaporated in vacuo. The residue was crystallizedfrom n-hexane to yield 3.8 g (41%) of n-propyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, melting at 61°-62°C. and having the structural formula: ##STR28##

The above method was used with minor modifications for the synthesis ofa number of other esters, i.e.:

Isopropyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate,crystallized from petroleum ether, melting at 59°-60° C.;

n-Butyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, crystallizedfrom a mixture of chloroform and hexane, melting at 48°-49° C.; and

Benzyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, crystallizedfrom a mixture of chloroform and hexane, melting at 73°-74° C.

n-Butyl 4-(2-hydroxy-3-tert-butylamino)propoxyphenylacetate was preparedsimilarly to the n-butyl ester described above, replacing theisopropylamine starting material in the last step with tert-butylamine.The crude ester was dissolved in dimethyl carbonate and a solution ofoxalic acid in dimethyl carbonate was added. The crystals were removedby filtration and recrystallized from acetone to yield 9 g(25%) ofn-butyl 4-(2-hydroxy-3-tert-butylamino)propoxyphenylacetate oxalatehydrate, melting at 112°-114° C.

All final products prepared above gave satisfactory elementary analysis±0.4% C, H, N. NMR and ir spectra were consistent with structure.

EXAMPLE 6

Cyclohexyl 4-hydroxyphenylacetate (9.18 g) in epichlorohydrin (50 mL)was refluxed for 2 hours in the presence of DBU (1 mL). The mixture wasevaporated in vacuo, and the residue was refluxed with isopropylamine(20 mL) in acetonitrile (100 mL) for 4 hours, then evaporated in vacuo.A solution of oxalic acid in acetone was added to a solution of theresidue in acetone. The crystals were removed by filtration andrecrystallized from acetone to yield 6.05 g of cyclohexyl4-(2-hydroxy-3-isopropyl amino)propoxyphenylacetate oxalate 3/4 hydrate,melting at 131°-132° C. Elementary analysis and NMR and ir spectra wereconsistent with structure. The free base has the formula: ##STR29##

EXAMPLE 7

2,6-Dimethylcyclohexyl 4-hydroxyphenylacetate (8.00 g) was refluxed withepichlorohydrin (50 mL) in the presence of DBU (1 mL) for 2 hours, andevaporated in vacuo. The residue was refluxed with isopropylamine (20mL) in acetonitrile (100 mL) for 4 hours, then evaporated to dryness invacuo. To a solution of the residue was added a solution of oxalic acidin acetone, and the crystals were removed by filtration, washed withacetone, and recrystallized from acetone to yield 6.4 g of2,6-dimethylcyclohexyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate oxalate hydrate,melting at 89°-91° C. Elementary analysis and NMR and ir spectra wereconsistent with structure. The free base has the structural formula:##STR30##

EXAMPLE 8

3,3,5,5-Tetramethylcyclohexyl 4-hydroxyphenylacetate (10.86 g) wasdissolved in 8% methanolic KOH solution (20 m L), and evaporated todryness in vacuo. Epichlorohydrin (500 mL) was added to the residue, andthe mixture was refluxed for 2 hours, then evaporated in vacuo. Theresidue was extracted with benzene (200 mL), washed, dried, evaporatedin vacuo, and refluxed with isopropyl amine (20 mL) in acetonitrile for8 hours, then evaporated in vacuo. A solution of oxalic acid in acetonewas added to a solution of the residue in acetone. The crystals wereremoved by filtration and recrystallized from acetone to yield 8.06 g of3,3,5,5-tetramethylcyclohexyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate oxalate 3/4 hydrate,melting at 96°-97° C. Elementary analysis and NMR and ir spectra wereconsistent with structure. The free base has the structural formula:##STR31##

EXAMPLE 9

A solution of 4-(2-hydroxy-3-isopropylamino)propoxyphenyl acetic acid(13.4 g) in cyclohexyl alcohol (50 mL) was saturated with hydrogenchloride gas under cooling, then was heated at 70° C. for 4 hours.Excess cyclohexyl alcohol was evaporated in vacuo. The residue wasdissolved in water (200 mL) and adjusted to pH 9 with 10% Na₂ CO₃solution. The oily material was extracted with chloroform (200 mL),washed with water, dried, and evaporated in vacuo. The residue wasdissolved in acetone (100 mL) and adjusted to pH 5 with 10% oxalic acidin acetone. The crystals were removed by filtration, washed withacetone, dried and recrystallized from acetone to yield 11.8 g ofcyclohexyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate oxalate3/4 hydrate, melting at 131°-132° C.

EXAMPLE 10

Use of the starting materials indicated below in the generalesterification procedure described in EXAMPLE 1 affords the indicatedproducts:

      -      ROH + HOOCC.sub.n      H.sub.2nArOH     ##STR32##      ROOCC.sub.n      H.sub.2nArOH      ##STR33##      ##STR34##      ##STR35##      (1)      ##STR36##      ##STR37##      ##STR38##      (2)      ##STR39##      ##STR40##      ##STR41##      (3)      ##STR42##      ##STR43##      ##STR44##      (4)      ##STR45##      ##STR46##      ##STR47##      (5)      ##STR48##      ##STR49##      ##STR50##      (6)      ##STR51##      ##STR52##      ##STR53##      (7)      ##STR54##      ##STR55##      ##STR56##      (8)      ##STR57##      ##STR58##      ##STR59##      (9)      ##STR60##      ##STR61##      ##STR62##      (10)     CH.sub.3 SCH.sub.2      OH     ##STR63##      ##STR64##      (11)     CH.sub.3 SCH.sub.2      OH     ##STR65##      ##STR66##      (12)      ##STR67##      ##STR68##      ##STR69##      (13)      ##STR70##      ##STR71##      ##STR72##      (14)     CH.sub.3 SCH.sub.2      OH     ##STR73##      ##STR74##      ##STR75##      ##STR76##      ##STR77##      (16)      ##STR78##      ##STR79##      ##STR80##      (17)      ##STR81##      ##STR82##      ##STR83##      (18)      ##STR84##      ##STR85##      ##STR86##      (19)      ##STR87##      ##STR88##      ##STR89##      (20)      ##STR90##      ##STR91##      ##STR92##      (21)      ##STR93##      ##STR94##      ##STR95##      (22)      ##STR96##      ##STR97##      ##STR98##      (23)      ##STR99##      ##STR100##      ##STR101##      (24)      ##STR102##      ##STR103##      ##STR104##      (25)      ##STR105##      ##STR106##      ##STR107##      (26)      ##STR108##      ##STR109##      ##STR110##      (27)      ##STR111##      ##STR112##      ##STR113##      (28)      ##STR114##      ##STR115##      ##STR116##      (29)      ##STR117##      ##STR118##      ##STR119##      (30)     CH.sub.3 CH.sub.2 SCH.sub.2      OH     ##STR120##      ##STR121##      (31)      ##STR122##      ##STR123##      ##STR124##      (32)     CH.sub.3 SCH.sub.2      OH     ##STR125##      ##STR126##      (33)      ##STR127##      ##STR128##      ##STR129##      (34)      ##STR130##      ##STR131##      ##STR132##      (35)      ##STR133##      ##STR134##      ##STR135##      (36)      ##STR136##      ##STR137##      ##STR138##      (37)      ##STR139##      ##STR140##      ##STR141##      (38)      ##STR142##      ##STR143##      ##STR144##      (39)      ##STR145##      ##STR146##      ##STR147##      (40)      ##STR148##      ##STR149##      ##STR150##      (41)      ##STR151##      ##STR152##      ##STR153##      (42)      ##STR154##      ##STR155##      ##STR156##      (43)      ##STR157##      ##STR158##      ##STR159##      (44)      ##STR160##      ##STR161##      ##STR162##      (45)      ##STR163##      ##STR164##      ##STR165##      (46)      ##STR166##      ##STR167##      ##STR168##      (47)      ##STR169##      ##STR170##      ##STR171##      (48)      ##STR172##      ##STR173##      ##STR174##      (49)      ##STR175##      ##STR176##      ##STR177##      (50)      ##STR178##      ##STR179##      ##STR180##      (51)

EXAMPLE 11

Substitution of an equivalent quantity of the products of EXAMPLE 10 inthe general procedures of EXAMPLE 6 [i.e. reaction of a compound of theformula ROOC--C_(n) H₂ n--Ar--OH with an epihalogenohydrin such asepichlorohydrin, followed by reacting the resultant intermediate(s) withthe appropriate primary amine] affords, after appropriate isolation, thefollowing compounds of the invention:

    __________________________________________________________________________     STARTING MATERIAL                                                                                         ##STR181##                                       __________________________________________________________________________     ##STR182##               (1)                                                                              ##STR183##                                        ##STR184##               (2)                                                                              ##STR185##                                        ##STR186##               (3)                                                                              ##STR187##                                        ##STR188##               (4)                                                                              ##STR189##                                        ##STR190##               (5)                                                                              ##STR191##                                        ##STR192##               (6)                                                                              ##STR193##                                        ##STR194##               (7)                                                                              ##STR195##                                        ##STR196##               (8)                                                                              ##STR197##                                        ##STR198##               (9)                                                                              ##STR199##                                        ##STR200##              (10)                                                                              ##STR201##                                        ##STR202##              (11)                                                                              ##STR203##                                        ##STR204##              (12)                                                                              ##STR205##                                        ##STR206##              (13)                                                                              ##STR207##                                        ##STR208##              (14)                                                                              ##STR209##                                        ##STR210##              (15)                                                                              ##STR211##                                        ##STR212##              (16)                                                                              ##STR213##                                        ##STR214##              (17)                                                                              ##STR215##                                        ##STR216##              (18)                                                                              ##STR217##                                        ##STR218##              (19)                                                                              ##STR219##                                        ##STR220##              (20)                                                                              ##STR221##                                        ##STR222##              (21)                                                                              ##STR223##                                        ##STR224##              (22)                                                                              ##STR225##                                        ##STR226##              (23)                                                                              ##STR227##                                        ##STR228##              (24)                                                                              ##STR229##                                        ##STR230##              (25)                                                                              ##STR231##                                        ##STR232##              (26)                                                                              ##STR233##                                        ##STR234##              (27)                                                                              ##STR235##                                        ##STR236##              (28)                                                                              ##STR237##                                        ##STR238##              (29)                                                                              ##STR239##                                        ##STR240##              (30)                                                                              ##STR241##                                        ##STR242##              (31)                                                                              ##STR243##                                        ##STR244##              (32)                                                                              ##STR245##                                        ##STR246##              (33)                                                                              ##STR247##                                        ##STR248##              (34)                                                                              ##STR249##                                        ##STR250##              (35)                                                                              ##STR251##                                        ##STR252##              (36)                                                                              ##STR253##                                        ##STR254##              (37)                                                                              ##STR255##                                        ##STR256##              (38)                                                                              ##STR257##                                        ##STR258##              (39)                                                                              ##STR259##                                        ##STR260##              (40)                                                                              ##STR261##                                        ##STR262##              (41)                                                                              ##STR263##                                        ##STR264##              (42)                                                                              ##STR265##                                        ##STR266##              (43)                                                                              ##STR267##                                        ##STR268##              (44)                                                                              ##STR269##                                        ##STR270##              (45)                                                                              ##STR271##                                        ##STR272##              (46)                                                                              ##STR273##                                        ##STR274##              (47)                                                                              ##STR275##                                        ##STR276##              (48)                                                                              ##STR277##                                        ##STR278##              (49)                                                                              ##STR279##                                        ##STR280##              (50)                                                                              ##STR281##                                        ##STR282##              (51)                                                                              ##STR283##                                       __________________________________________________________________________

EXAMPLE 12

Treatment of the sulfur-containing compounds of the invention listedbelow with one equivalent of m-chloroperbenzoic acid affords thecorresponding sulfinyl derivatives of the invention, while treatment ofthe thio compounds with two equivalents of m-chloroperbenzoic acidyields the corresponding sulfonyl derivatives of the invention.

      - THIO COMPOUND SULFINYL COMPOUND SULFONYL COMPOUND      ##STR284##      (12)      ##STR285##      ##STR286##      ##STR287##      (15)      ##STR288##      ##STR289##      ##STR290##      (31)      ##STR291##      ##STR292##      ##STR293##      (33)      ##STR294##      ##STR295##

EXAMPLE 13

A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), methanol (50mL) and SOCl₂ (2 mL, 0.028 mol) was refluxed for 3 hours. The residuewas cooled, diluted with ethyl acetate (20 mL), washed first withaqueous 5% Na₂ CO₃ solution and then twice with water (100 mL), thendried over anhydrous MgSO₄, filtered and evaporated in vacuo to givemethyl 4-hydroxyphenylacetate as an oil.

A solution of methyl 4-hydroxyphenylacetate (8.72 g) in epichlorohydrin(50 mL) was refluxed in the presence of DBU (2 mL, 0.014 mol) for 2hours. Excess epichlorohydrin was removed under vacuum. The oily productwas refluxed with isopropylamine (20 mL, 0.23 mol) in acetonitrile (100mL) for 4 hours, then was evaporated in vacuo. The free amine base whichseparated was taken up in acetone (25 mL) and a molar equivalent amountof oxalic acid was added dropwise. The acetone solution was concentratedand the residue was partitioned between ether (100 mL) and 1M aqueousKOH solution (100 mL). The ether layer was separated, 1N HCl (30 mL) wasadded, the acidic layer was separated, and ethyl ether (100 mL) and 1Maqueous KOH solution (30 mL) were added to it. The resultant ether layerwas separated, dried over anhydrous MgSO₄, filtered and evaporated invacuo. The oily residue (5.43 g, 0.01 mol) was dissolved in 25 mL ofacetone, and oxalic acid (2.5 go 0.01 mol) in acetone was added dropwisewith stirring and cooling. The product which separated was filtered,dried and crystallized from a mixture of ethyl acetate and acetone. Theresultant oxalate salt of methyl4-(2-hydroxy-3-isopropylamino)-propoxyphenylacetate, obtained in 82%yield, melted at 58°-59° C. NMR and elemental analysis confirmed theidentity of the product.

EXAMPLE 14

A mixture of 4-hydroxyphenylacetic acid (g.12 g, 0.06 mol), absoluteethanol (50 mL) and SOCl₂ (2 mL, 0.028 mol) was refluxed for 3 hours.The residue was cooled, diluted with ethyl acetate (200 L), washed firstwith dilute aqueous sodium bicarbonate (100 mL) and then twice withwater (100 mL), then was dried over anhydrous MgSO₄, filtered andevaporated in vacuo. Ethyl 4-hydroxyphenylacetate was obtained as anoil.

A solution of ethyl 4-hydroxyphenylacetate (9.20 g) in acetone (50 mL)and epichlorohydrin (50 mL) was refluxed in the presence of DBU (2 mL,0.014 mol) for 4 hours. Excess epichlorohydrin was removed under reducedpressure. The resultant oil was taken up in acetonitrile (100 mL),isopropylamine (20 mL, 0.23 mol) was added and the reaction mixture wasrefluxed for 4 hours. Evaporation in vacuo afforded an oil. The oil wastaken up i n acetone (50 mL ) and an equivalent amount of oxalic acid inacetone (25 mL) was added gradually. A white crystalline by-productmelting at 202°-204° C. separated on cooling. The acetone mother liquorwas evaporated and the residue was partitioned between ethyl ether (100mL) and 1M aqueous KOH solution (100 mL). The ether layer was separatedand washed with 1M HCl (50 mL). The acid layer was partitioned betweenanhydrous ethyl ether (100 mL) and 1M aqueous KOH solution (100 mL). Theether layer was separated, dried over anhydrous MgSO₄, filtered andevaporated to dryness. The residue (5.30 g) was dissolved in acetone (25mL). An equivalent amount of oxalic acid (2.52 g, 0.1 mol) was dissolvedin acetone (25 mL ) and was added dropwise, with constant stirring. Thereaction mixture was allowed to cool, and the product which separatedwas filtered and crystallized from a mixture of acetone and ethylacetate. The resultant oxalate salt of ethyl4-(2-hydroxy-3-isopropylamino)propoxyphenyl) acetate melted at 82°-84°C. NMR and elemental analysis confirmed the identity of the product.

EXAMPLE 15

A mixture of 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol ), cyclohexylalcohol (6 g, 0.06 mol), p-toluenesulfonic acid (1 g, 0.006 mol) andbenzene (300 mL) was refluxed with continuous water separation for 8hours. The mixture was cooled and washed, first with aqueous 5% Na₂ CO₃solution, then twice with water, then was dried over anhydrous MgSO₄.Evaporation of the solvent in vacuo gave cyclohexyl4-hydroxyphenylacetate.

A solution of cyclohexyl 4-hydroxyphenylacetate in epichlorohydrin (30mL) was refluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol).Excess epichlorohydrin was removed in vacuo. The residue was refluxedwith isopropylamine (20 mL, 0.23 mol) in acetonitrile (100 mL) for 4additional hours, then the mixture was allowed to stand at roomtemperature for 24 hours and evaporated in vacuo. The residue waspartitioned between ethyl ether (100 mL) and aqueous 1M KOH solution(100 mL). The ether layer was separated and 1N HCl (30 mL) was added toit. The acid layer was separated and washed with ethyl ether (100 mL).The resultant ether layer was separated, washed with aqueous 1N KOHsolution (30 mL) and water and then dried over anhydrous MgSO₄, filteredand evaporated in vacuo. The residue was dissolved in acetone (50 mL)and an equivalent amount of oxalic acid in acetone (25 mL) was addeddropwise, with stirring. The oxalate salt of cyclohexyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which was isolated in50.2% yield melted at 130°-132° C. The free base has the structuredepicted in EXAMPLE 6.

EXAMPLE 16

3,3,5,5-Tetramethylcyclohexanol (7.81 g, 0.05 mol),4-hydroxyphenylacetic acid (7.6 g, 0.05 mol), p-toluenesulfonic acid (2g) and benzene (200 mL) were refluxed with continuous water separationfor 8 hours. The reaction mixture was evaporated, the oily residue wasdissolved In ethyl acetate (100 mL), washed first with aqueous 5% NaHCO₃solution (100 mL) and then twice with water (200 mL), then dried overanhydrous MgSO₄. The solvent was evaporated under reduced pressure togive 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate as a solid(7.00 g, 82.0% yield).

3,3,5,5-Tetramethylcyclohexyl 4-hydroxyphenylacetate was taken up inacetone (25 mL), combined with epichlorohydrin (20 mL) with stirring andrefluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol). Thereaction mixture was evaporated. The oily residue was taken up inacetonitrile (50 mL). Isopropylamine (20 mL, 0.23 mol) was added and thereaction mixture was refluxed for 4 hours, then was evaporated to givethe crude free amine base as an oil. The oil was taken up in acetone andan equivalent amount of oxalic acid (5.2 g, 0.05 mol) was added. Theacetone solution was concentrated and partitioned between ether (100 mL)and aqueous 1M KOH solution (50 mL). The ether layer was separated andwashed with 1M HCl (50 mL). The acidic layer was basified with aqueous1N KOH solution and extracted with fresh anhydrous ethyl ether. Theether layer was separated, dried over anhydrous MgSO₄, filtered andevaporated. The residue was dissolved in acetone (25 mL), an equivalentamount of oxalic acid in acetone was added, and the oxalate salt of3,3,5,5-tetramethylcyclohexyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which separated oncooling was isolated. The product melted at 96°-98° C. The free base hasthe structure shown in EXAMPLE 8.

EXAMPLE 17

To a solution of 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol) in ethanol(100 mL) was added potassium hydroxide (2.8 g, 0.05 mol), with stirringand ice cooling. The white crystalline potassium salt which wasseparated by filtration melted at about 275°-277° C. and was obtained in90.5% yield.

The potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.05 mL) wassuspended in dimethylformamide (25 mL). Chloromethyl pivalate (7.53 g,0.05 mol) was added and the reaction mixture was stirred at roomtemperature for 24 hours. The reaction mixture was poured into ice waterand extracted with ethyl acetate (100 mL). The ethyl acetate layer waswashed, first with aqueous 5% NaHCO₃ (100 mL) and then twice with water,then was dried over anhydrous MgSO₄, filtered and evaporated to yieldpivalyloxymethyl 4-hydroxyphenylacetate, melting at 159°-161° C. (yield70.2%).

EXAMPLE 18

Pivalyloxymethyl 4-hydroxyphenylacetate (7.0 g, 0.05 mol) was dissolvedin acetone (50 mL) and epichlorohydrin (40 mL) was added. That mixturewas refluxed in the presence of DBU (1 mL, 0.007 mol) for 2 hours, thenwas allowed to stir at room temperature overnight. The reaction mixturewas evaporated in vacuo. The epoxide residue was dissolved inacetonitrile (80 mL), isopropylamine (20 mL, 0.23 mol) was added and thereaction mixture was stirred overnight at room temperature, refluxed for4 hours and evaporated. The free amine base was purified by extractionwith acid and base from ether. After evaporation of the ether, theresidual oil was partitioned between ethyl ether and 1M aqueous KOHsolution, the ether layer was washed with 1M HCl, the acidic layer wasbasified with 1M aqueous KOH solution, and fresh anhydrous ethyl etherwas added. The ether layer was separated, dried over anhydrous MgSO₄ andfiltered. An equivalent amount of oxalic acid in acetone was addeddropwise. The oxalate salt which separated was filtered and dried. Itmelted at 123°-124° C. The free base, pivalyloxymethyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, has the structure:##STR296## The identity of the product was confirmed by NMR andelemental analysis.

EXAMPLE 19

1-Adamantaneethanol (10 g, 0.05 mol), 4-hydroxyphenylacetic acid (8.43g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxedin benzene (100 mL) with continuous water separation for 8 hours, thenallowed to stir overnight. The residue was washed, first with 5% aqueoussodium bicarbonate solution (50 mL) and then twice with water (50 mL),then was dried over anhydrous MgSO₄ and filtered. The filtrate wasconcentrated in vacuo. The product, (adamant-1-yl)ethyl4-hydroxyphenylacetate, was taken up in epichlorohydrin (50 mL) andrefluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol). Theresidue was dissolved in acetonitrile (100 mL) and refluxed withisopropylamine (20 mL, 0.23 mol) for 4 hours. The reaction mixture wasevaporated in vacuo and the residue was partitioned between ethyl ether(100 mL) and 0.5N aqueous NaHCO₃ solution (100 mL). The ether layer wasseparated and 1N HCl (30 mL) was added to it. The aqueous layer wasseparated, 1M aqueous KOH solution (30 mL) was added and the solutionwas extracted with ether (100 mL). The aqueous layer was discarded andthe ether layer was dried over anhydrous MgSO₄, filtered and evaporatedin vacuo. The oily product was dissolved in acetone (25 mL) and anequivalent quantity of oxalic acid in acetone (25 mL) was addeddropwise, with stirring. The acetone was evaporated in vacuo and theresidue was partitioned between ether (100 mL) and 1M aqueous KOHsolution (100 mL). The ether layer was separated, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The oily residue wasdissolved in acetone (25 mL) and an equivalent amount of oxalic acid inacetone (25 mL ) was added dropwise, with stirring. The product whichseparated was removed by filtration, dried and recrystallized fromacetone. The oxalate salt of (adamant-1-yl)ethyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate thus obtained meltedat 95°-97° C. Yield 70.9%. The free base has the structure: ##STR297##NMR and elemental analysis were consistent with the assigned structure.

EXAMPLE 20

1-Adamantanemethanol (8.31 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxedin benzene (100 mL) with continuous water separation for hours. Thereaction mixture was allowed to cool with stirring overnight, then waswashed, first with water (100 mL), then with aqueous 5% NaHCO₃ solution(100 mL), then twice more with water (100 mL). Drying over anhydrousMgSO₄, filtering and concentrating in vacuo afforded (adamant-1-yl)methyl 4-hydroxyphenyl acetate, which was then combined withepichlorohydrin (50 mL) and refluxed for 2 hours in the presence of DBU(1 mL, 0.007 mol ). Excess epichlorohydrin was removed in vacuo. Theoily residue was dissolved in acetonitrile (100 mL) and combined withisopropylamine (20 mL, 0.23 mol). The resultant reaction mixture wasrefluxed for 4 hours. The oily brown residue was partitioned betweenethyl ether (100 mL) and 1M aqueous KOH solution (100 mL). The etherlayer was separated and to it was added 1N HCl (30 mL). The resultantacid layer was separated and to it were added ethyl ether (100 mL ) and1M aqueous KOH solution (30 mL). The resultant ether layer wasseparated, dried over anhydrous MgSO₄, filtered and evaporated in vacuoto give the free amine base as a crude product. The crude product (5.16g, 72.5% yield) was dissolved in acetone (25 mL), and oxalic acid (1.8g) in acetone (25 mL) was added dropwise, with stirring. The mixture wasallowed to stir for 24 hours with additional acetone. The acetonesolution was evaporated and the oily residue was partitioned betweenether (100 mL) and 1M aqueous KOH solution (100 mL). The ether solutionwas dried over anhydrous MgSO₄, filtered and concentrated. The oilyresidue was dissolved in acetone and an equivalent amount of oxalic acidin acetone was added dropwise. The oxalate salt of (adamant-1-yl)methyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which separated wasremoved and dried. It melted at 55°-57° C. NMR and elemental analysiswere consistent with structure. The free base has the formula:##STR298##

EXAMPLE 21

2-Norboranemethanol (6.34 g, 0.05 mol ), 4-hydroxyphenylacetic acid (7.6g, 0.05 mol), p-toluenesulfonic acid (2 g, 0.006 mol) and benzene (100mL) were refluxed with continuous water separation for 8 hours. Thesolvent was evaporated and the residue was dissolved in ethyl acetate(100 mL) and washed, first with 5% aqueous NaHCO₃ solution (100 mL),then twice with water (200 mL). Drying over anhydrous MgSO₄, filteringand evaporation left an oily residue, identified by NMR as the desired(norborn-2-yl)methyl 4-hydroxyphenylacetate. That product was taken upin acetone (50 mL), epichlorohydrin (40 mL) was added, and the reactionmixture was refluxed for 2 hours in the presence of DBU (2 mL, 0.007mol). The reaction mixture was evaporated in vacuo and the residual oilwas taken up in acetonitrile (100 mL). Isopropylamine (20 mL, 0.23 mol)was added and the reaction mixture was refluxed for 4 hours, thenevaporated to give the free amine base as an oil. The oil was dissolvedin acetone (50 mL) and an equivalent amount of oxalic acid in acetone(25 mL) was added dropwise with stirring. A white crystalline by-productmelting at 198°-200° C. separated and was discarded. The acetone wasevaporated in vacuo and the oil thus obtained was partitioned betweenethyl ether (100 mL) and 1M aqueous KOH solution (100 mL). The etherlayer was separated and 1M HCl (50 mL) was added. The acidic layer wasseparated, neutralized with 1M aqueous KOH solution (50 mL) andextracted with ethyl ether (100 mL). The ether layer was dried overanhydrous MgSO₄, filtered and evaporated to give the free amine base asan oil. Water (25 mL) was added to the oil; then oxalic acid (5.4 g,0.01 mol) in acetone (25 mL) was added dropwise, with constant stirring.The oxalate salt of (norborn-2-yl)methyl4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which separated aftercooling was washed with acetone (200 mL) and crystallized from a mixtureof ethyl acetate and acetone. It melted at 68°-70° C. The correspondingfree base has the structure: ##STR299## Elemental analysis and NMR wereconsistent with the assigned structure.

EXAMPLE 22

The potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.1 mol) wastaken up in a mixture of dimethylsulfoxide (80 mL) andhexamethylphosphoramide (5.37 g, 0.1 mol). 2--Chloroacetamide (13.5 g,0.3 mol) was added and the reaction mixture was first stirred at roomtemperature for 24 hours, then heated for 1 hour. The reaction mixturewas evaporated, then cooled. The product which separated was taken up inethyl acetate (150 mL), stirred, filtered and evaporated. The oilyresidue was partitioned between ethyl acetate (100 mL) and water (100mL). The organic layer was separated, dried over anhydrous MgSO₄,filtered and evaporated to give the desired ester, carbamoylmethyl4-hydroxyphenylacetate, melting at 85°-87° C., in 48.8% yield.

Carbamoylmethyl 4-hydroxyphenylacetate (10.4 g, 0.01 mol) was taken upin acetone. Epichlorohydrin (40 mL) was added and the reaction mixturewas refluxed for 2 hours in the presence of DBU (2 mL, 0.014 mol). Themixture was then evaporated to give an oil, which was dissolved inacetonitrile (100 mL) and then refluxed with isopropylamine (20 mL, 0.23mol) for 4 hours. The resultant mixture was evaporated in vacuo to givethe desired free amine base as an oil. That oil was dissolved in acetoneand an equivalent amount of oxalic acid in acetone was added. Theacetone solution was concentrated and then partitioned between ethylether (100 mL) and 1M aqueous KOH solution (50 mL). The ether layer wasseparated and extracted with 1M HCl (50 mL). The resultant acidicsolution was neutralized with 1M aqueous KOH solution and extracted withethyl ether. The ether layer was separated, dried over anhydrous MgSO₄,filtered and evaporated. The residue was dissolved in acetone and anequivalent amount of oxalic acid in acetone was added. The oxalate saltof carbamoylmethyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetatewhich separated after cooling was removed by filtration and dried. Itmelted at 93°-95° C. The corresponding free base has the structuralformula: ##STR300## NMR and elemental analysis were consistent with theassigned structure.

In the examples which follow, reference numbers have been assigned tothe test compounds as indicated immediately below:

    ______________________________________                                        Compound No. Name                                                             ______________________________________                                         5           4-(2-Hydroxy-3-isopropylamino)pro-                                            poxyphenylacetic acid                                            10           Ethyl 4-(2-hydroxy-3-isopropylamino)-                                         propoxyphenylacetate                                             11           n-Propyl 4-(2-hydroxy-3-isopropyl-                                            amino)propoxyphenylacetate                                       12           Isopropyl 4-(2-hydroxy-3-isopropyl-                                           amino)propoxyphenylacetate                                       13           n-Butyl 4-(2-hydroxy-3-isopropyl-                                             amino)propoxyphenylacetate                                       14           Benzyl 4-(2-hydroxy-3-isopropyl-                                              amino)propoxyphenylacetate                                       15           Cyclohexyl 4-(2-hydroxy-3-isopropyl-                                          amino)propoxyphenylacetate oxalate                                            3/4 hydrate                                                      16           2,6-Dimethylcyclohexyl 4-(2-hydroxy-                                          3-isopropylamino)propoxyphenylacetate                                         oxalate hydrate                                                  17           3,3,5,5-Tetramethylcyclohexyl 4-(2-                                           hydroxy-3-isopropylamino)propoxy-                                             phenylacetate oxalate 3/4 hydrate                                18           n-Butyl 4-(2-hydroxy-3-tert-butyl-                                            amino)propoxyphenylacetate oxalate                                            hydrate                                                          ______________________________________                                    

EXAMPLE 23

Kinetic Studies.

Analytical Methods. A high pressure liquid chromatography (HPLC) methodwas developed for the determination of the rate constants. Thechromatographic analysis was performed In a system consisting of WatersAssociates Model 600-A Solvent Delivery System, Model U-6K Injector andModel 440 Dual Channel Absorbance Detector operated at 254 and 280 nm. A30 cm×3.9 mm (Internal diameter) reverse phase μBondpack C18 column(Waters Associates), operated at ambient temperature, was used for allseparations. When plasma samples were analyzed, the column was protectedwith a 2.3 cm×3.9 mm (Internal diameter) Guard Column (Waters) packedwith μBondpack C18/Corasil packing material. The mobile phase used forthe separation of 17 and its degradation product, 5, consisted of water,1-hexane sulfonic acid in acetic acid (B-6 reagent, Waters), 0.1Mtriethanolamine and methanol (100:1:100:799). At a flow rate of 2.0mL/minute, 17 had a retention time of 3.95 minutes and 5 of 1.34minutes. For the separation of compounds 10-16 and 18 and theirdegradation product 5, a mobile phase consisting of water, 1-hexanesulfonic acid in acetic acid (B-6 reagent, Waters), 0.1M triethanolamineand methanol (390:1:10:599) was used. At a flow rate of 2.0 mL/minute,12 had a retention time of 3.79 minutes, 14 or 4.80 minutes, 10 of 2.77minutes, 11 of 3.85 minutes, 13 of 5.30 minutes, 5 of 1.48 minutes and18 of 8.39 minutes.

All solvents and reagents used were of UV or analytical reagent gradeand were used as obtained. Water was passed through an ion exchange bedand then distilled.

Determination of the Hydrolytic Rate Constants in Aqueous Solutions. A0.01M phosphate buffer and 0.01N sodium hydroxide solution were preparedfrom freshly distilled deionized water. This ionic strength wasmaintained at 0.1M with sodium chloride. The pH of the phosphate bufferwas determined at 37.0° C. with a pH meter standardized at thistemperature. For determination of the hydrolytic rate constants, a freshconcentrated solution of the ester in methanol was added to thehydrolytic medium previously equilibrated to the desired temperature andmixed thoroughly to result in an initial concentration of about 5×10⁻⁴mol. liter⁻¹. All reactions were run under pseudo first orderconditions. Samples of 25 μL were injected into the column at varioustime intervals and the pseudo first order rate constants were determinedfrom disappearance of the compound by linear regression of naturallogarithm of the peak height versus time plots. The half-life andstandard error of the rate constant were calculated for each run. Theresults in 0.01N aqueous sodium hydroxide solution at pH 12.0 and 27.3°C. are listed in TABLE I below.

                  TABLE I                                                         ______________________________________                                        The Observed Pseudo First order Hydrolytic Rate Con-                          stants (k), Half-Lives (t1/2) and the Initial Concen-                         trations (C.sub.0) in 0.01 N Sodium Hydroxide at pH 12.0,                     Ionic Strength 0.10 M (NaCl) and 27.3 ± 0.2° C.                     Compound                                                                              k (min.sup.-1)                                                                              t1/2 (min.)                                                                             C.sub.0 (mol. liter.sup.-1)                   ______________________________________                                        10      0.117 ± 0.001.sup.a                                                                      5.91      4.5 × 10.sup.-4                         11      0.103 ± 0.001                                                                            6.73      4.6 × 10.sup.-4                         12      2.07 ± 0.03 × 10.sup.-2                                                            33.5      9.8 × 10.sup.-4                         13      9.27 ± 0.07 × 10.sup.-2                                                            7.48      5.0 × 10.sup.-4                         14      0.208 ± 0.004.sup.a                                                                      3.33      2.2 × 10.sup.-4                         15      4.96 ± 0.03 × 10.sup.-2                                                            14.0      1.7 × 10.sup.-4                         16      9.71 ± 0.27 × 10.sup.-4                                                            7.14      8.3 × 10.sup.-5                                 1.09 ± 0.06 × 10.sup.-2                                                            63.3      2.8 × 10.sup.-5                         17      1.56 ± 0.04 × 10.sup.-2                                                            44.4      3.0 × 10.sup.-5                         18      7.19 ± 0.04 × 10.sup.-2                                                            9.64      8.l × 10.sup.-4                         ______________________________________                                         .sup.a Average of three runs ± SEM. The rest of data are the average o     four runs ± SEM.                                                      

In 0.01M phosphate buffer at pH 7.4 and 37° C., the compounds arehydrolyzed very slowly. The half-life of 14 under these conditions was13 days and that of 11 was 8.7 days.

Determination of the Enzymatic Hydrolytic Cleavage Rates In HumanPlasma, The freshly collected plasma used was obtained from the CivitanRegional Blood Center, Inc. (Gainesville, Fla.) and contained about 80%plasma diluted with anticoagulant citrate phosphate dextrose solution,U.S.P. The plasma was stored in a refrigerator and used within one weekfrom the date was collected. During the experiment the hydrolyticactivity of the plasma was tested by determining effect on thehydrolytic cleavage rates of 17 and was found to be constant.

A portion of 50 μL of a freshly prepared solution of the compound inmethanol was added to 10 mL plasma, previously equilibrated at 37.0° C.In a water bath, and mixed thoroughly to result in an initialconcentration of 1×10⁻³ mol. liter⁻¹. One mL samples of plasma werewithdrawn from the test medium, mixed immediately with 4.0 mL ice cold95% v/v ethanol, centrifuged and the supernatant analyzed by HPLC. Thefirst order hydrolytic rate constant was determined as before in theaqueous solutions and the results are listed in TABLE II below.

                  TABLE II                                                        ______________________________________                                        The Observed First Order Hydrolytic Rate Constants (k),                       Half-Lives (t1/2) and the Initial Concentrations (C.sub.0 in                  Human Plasma at 37.0 ± 0.1° C. The Hydrolytic Rate                  Constants Were Obtained by Following the Disappearance                        of the Compounds by HPLC as a Function of Time.                               Com-                                                                          pound  k (min.sup.-1) t1/2 (min)                                                                              C.sub.O (mol. liter.sup.-1)                   ______________________________________                                        10     0.238 ± 0.010.sup.a                                                                       2.91      1.6 × 10.sup.-3                         11     0.143 ± 0.005                                                                             4.86      2.5 × 10.sup.-3                         12     0.414 ± 0.001 × 10.sup.-2                                                           1.67 × 10.sup.2                                                                   1.1 × 10.sup.-3                         13     0.612 ± 0.016                                                                             1.13      1.4 × 10.sup.-3                         14     0.236 ± 0.007.sup.a                                                                       2.93      1.4 × 10.sup.-3                         15     1.46 ± 0.15.sup.b                                                                         0.47      5.8 × 10.sup.-4                                --.sup.c       --        5.9 × 10.sup.-4                         16     1.64 ± 0.14 × 10.sup.-2                                                             42.2      2.0 × 10.sup.-4                         17     0.566 ± 0.027                                                                             1.22      9.3 × 10.sup.-4                         18     0.351 ± 0.019                                                                             1.98      1.5 × 10.sup.-3                         ______________________________________                                         .sup.a Average of three runs ± SEM.                                        .sup.b Average of four runs ± SEM.                                         .sup.c Essentially no change in the peak height over a period of three        hours.                                                                   

From the hydrolytic stabilities of esters 10-17 in aqueous solution atpH 12, it can be seen that the rate of hydroxide ton catalyzedhydrolysis is generally controlled by the relative steric hindrance atthe ester portion. Compound 16 was obtained as a 1:2 mixture of twoisomers, separable by HPLC, and in agreement with this, 16 showedbiphasic kinetics. While the starting alcohol was a mixture of isomers(potentially six), the ester 16 contained only two of them (cis-, mostlikely di-equatorial and trans-, axial- equatorial dimethyl cyclohexanolderivatives). The latter one possibly was a d, l mixture, inseparable bysimple chromatography. It is assumed that the bulky ester group betweenthe two methyl functions is in equatorial position. The kinetic data areshown in TABLE I.

The relative hydrolysis rates in human plasma (TABLE II) show, however,some unexpected trends: The isopropyl ester 12 is hydrolyzed up to 100times more slowly then many of the other esters. The isomer of 16, whichis more stable in basic conditions, did not hydrolyze in the plasmawithin 3 hours. As expected, the presence of the t-butyl group on theamine did not affect the hydrolysis rates (13 vs. 18). It is evident,however, that except for the isopropyl derivative 12, the rest of theesters hydrolyzed very fast in the plasma.

EXAMPLE 24

Pharmacological Tests.

Initial Drug Screening Protocol. Thirty-two male Sprague-Dawley rats(Blue Spruce Farms) initially weighing 300-450 gm were divided intoseven different groups, each for a different drug to be tested: 12(n-4),14(n-4), 17(n-5), 13(n-4) and 18(n-3), corresponding to the designatedcompounds 12, 14, 17, 13 and 18 (number of animals), respectively. Theother two groups were controls (n=8, isoproterenol alone pretreated withcarrier) and those treated with a known β-blocker, di-propranolol (n=3).Ech animal was anesthetized with sodium pentobarbital (45 mg/kg) and thecarotid artery was cannulated with PE-50 tubing. The cannula wassubcutaneously threaded around the neck and exteriorized dorsallybetween the shoulder blades. The cannula was filled with a heparinsolution (300 μg/mL) and sealed with a solid 22 gauge stylet. Theanimals were housed in individual stainless steel cages, and two dayswere allowed for recovery from the surgery. Food and water were providedad libitum. On the day of the experiment, the blood pressure and heartrate of each rat were monitored with a pressure transducer (Narco-Biomodel P-1000) and the data recorded on a four-channel physiograph(Narco-Bio systems Marck IV). One hour was allowed as an equilibrationperiod before any drugs were administered. All beta blockers wereadministered intraperitoneally at a dose of 6 mg/kg. Compounds 12 and 14and di-propranolol were dissolved in normal saline while compounds 13,17 and 18 were dissolved in an ethanol: water solution (3:1). Dependingon the trial, controls were administered the appropriate carrier. Onehour after administration of the blocker, isoproterenol (Isuprel®,Wintrop Laboratories) was administered subcutaneously at a dose of 25μg/kg. Blood pressures and heart rate also were recorded 3, 5, 10, Z5,20, 30, 45 and 60 minutes after isoproterenol administration. Bothcontrol and experimental animals were unrestrained and free moving intheir home cage throughout the experiment. FIG. 1 shows the results Interms of mean change In heart rate following administration ofIsoproterenol (25 μg/kg s.c.) for compounds 12(◯), 14(Δ), 17(▪), 13(□),18(⋄), d,l-propranolol () and the control vehicle (▴). A one-wayanalysis of variance (f29, 6) revealed no significant differences Inresting heart rates prior to administration of isoproterenol: 345±19;405±22; 372±19; 340±14; 307±7; 320±23 and 333±17 beat/minute,respectively. However, significant differences in the mean heart rateresponse amoung the 7 groups were observed: *p<0.005; **p<0.025.Comparisons between groups were made by the Newman-Keuls procedure withsignificance set at the 95% confidence interval. During the first 20minutes, the group administered compound 17 was significantly differentfrom both control- and compound 18-treated groups. Thepropranolol-treated group was significantly different for the first 30minutes. Additionally, the group administered compound 17 and thepropranolol-treated group were significantly different than the groupstreated with compound 12 and 18 at 10 through 45 minutes followingadministration of isoproterenol. All data are shown as mean±standarderror of the mean.

FIG. 3 shows the results in terms of mean change in blood pressurefollowing administration of isoproterenol (25 μg/kg s.c.). Symbols arethe same as those described for FIG. 1. Statistical analysis revealedthat compounds 14 and 13 were significantly lower (p<0.15) than thepropranolol and compound 12-treated groups. One-way analysis of variancedemonstrated that a significant difference between the seven groupsexisted at 10 and 15 minutes following administration of isoproterenol:*p<0.01; **p<0.025. At the 10-minute time interval, groups treated withcompounds 17 and 13 were significantly different from the group treatedwith compound 18. The group treated with compound 13 was also differentfrom the compound 12-treated group. At the 15-minute interval, the grouppretreated with compound 13 was significantly different from groupspretreated with compound 12, 18 and the control vehicle. Data are shownas mean±standard error of the mean.

Duration of Action Studies. An additional 38 male Sprague Dawley rats(Blue Spruce Farms) initially weighing 268 to 290 gm were anesthetizedwith sodium pentobarbital (45 mg/kg i.p.), and the carotid artery wascannulated as previously described. On the day of experimentation, aftera one-hour equilibration period, initial baseline conditions of basalheart rate and mean blood pressures were recorded. The beta blocker (17)was administered intraperitoneally at a dose of 6 mg/kg. The drug wasdissolved in an ethanol: water solution (3:1). This carrier wasadministered in the control rats isoproterenol (Isurprel®, WintropLaboratories) was then administered (25 μg/kg s.c.), either 15(n=13),60(n=12) or 90(n=13) minutes after the beta blocker was administered.Blood pressures and heart rates were recorded at 3, 5, 10, 15, 20, 30,45 and 60 minutes after isoproterenol administration in all threetrials. Both control and experimental animals were unrestrained and freemoving in their home cages throught the experiment. Heart rates and meanblood pressure were calculated from the data and a one-way ANOVA wasdetermined at each time interval. The results are shown in FIG. 2 forcontrol vehicle () and compound 17 at 15(◯), 60(▴) and 90(Δ) minutesprior to isoproterenol administration at time zero. Resting heart rateswere similar in all 4 groups prior to administration of isoproterenol;342±12; 375±14; 372±19 and 385±17 beats/minute, respectively. One-wayanalysis of variance (f40, 3) revealed a significant difference inresponse between the 4 groups during the 45 minutes followingadministration of isoproterenol: *p<O.005; p<0.025. Comparison betweengroups demonstrated an attentuated heart rate response when compound 17was administered either 15 or 60 minutes prior to the administration ofisoproterenol. Data are shown as mean±standard error of the mean.

Cardiovascular Experiments.

Method. Healthy, mongrel dogs were anesthetized with a combination ofmorphine sulfate (2.0 mg/kg, subcutaneously) followed in 20 minutes withpentabarbital sodium (15 mg/kg, intravenously). Supplementalpentabarbital was given as necessary. A femoral vein was catheterizedwith polyethylene tubing to the level of the heart for Injecting drugsolutions. A polyethylene tube filled with heparinized saline wasinserted through the femoral artery and advanced to the thoracic aortafor the measurement of arterial pressure. The left carotid artery wascannulated with a Millar® transducer-tip catheter for measurement ofleft ventricular pressure (LVP). The rising slope of the LVP signal wasdifferentiated to give dr/dr, an estimate of myocardial contractility.Heart rate was determined via a Grass cardiotachometer triggered by theR wave of the lead II EKG. All variables were recorded on a Grasspolygraph.

Dose-response curves were constructed for each experimental variable tograded i.v. doses of the β-adrenergic agonist, isoproterenol. A periodof 3-5 minutes was allowed after each injection for variables to returnto base-line. Following this, one of the four experimental β-adrenergicblocking agents was given i.v. over a one-minute period. Abbreviateddose-response curves (2-3 dose points) were again constructed toisoproterenol at 15, 30, 45, 60, 75 and 90 minutes after theadministration of the test blockers. Using a 50-beat per minute (bpm)increase In heart rate as criteria, the degree of blockade wasdetermined by dividing the dose of isoproterenol needed to produce a SObpm increase at various times following administration of an antagonistby the dose needed for this effect during the control period. The dosesof the experimental β-adrenergic antagonists given were determined fromprevious experiments to produce an approximate two- or four-foldblockade of the heart rate response to isoproterenol. Results are givenin TABLE III and FIG. 4.

                  TABLE III                                                       ______________________________________                                        Peak Antagonist Activity.sup.a and Duration of Action.sup.b of                Adrenergic Blocking Agents                                                             Maximal blockade.sup.a                                                                         Duration.sup.b                                      Compound   Range   Mean       Range Mean                                      number     (min)   (min)      (min) (min)                                     ______________________________________                                        10         (15-15) 15         45-60 ˜50                                 15         (15-30) 20         75-90 ˜85                                 16         (15-60) 38         45-90 ˜65                                 17         (30-60) 40         45-90 ˜70                                 ______________________________________                                         .sup.a Time necessary to reach maximal blockade (15 minute measurements).     Data were obtained from doseresponse curves before and after 1 mg/kg of       each agent.                                                                   .sup.b Time after each adrenergic blocking agent (1 mg/kg) at which           response to isoproterenol had returned to control levels.                

In FIG. 4, the increase in heart rate (Δbpm) is shown for dogsadministered 1 mg/kg of compound 17(∇--∇), 10(Δ--Δ), 16(□--□), 15(*--*)and control (◯--◯). Baseline values were all around 117±6 bpm. Errorbars represent S.E. of mean.

Discussion of Pharmacological Tests.

Since, due to high esterase activity In the liver and other organs,esters generally hydrolyze faster In the whole body than in vitro inplasma, and since acid 5 is inactive, not much β-antagonist activitywould be expected, unless there is not much correlation between theplasma concentration of the active species and the actual activity(affinity and binding to the receptors). Five compounds, 12, 13, 14, 17and 18, were selected for in vivo studies in rats, and compared topropranolol, a well-accepted standard for β-blockers. In the first setof experiments, the compounds were administered intraperitoneally at 6mg/kg dose, and blood pressure and heart rate were monitored. One hourafter administration of the blocker, an agonist, isoproterenol, wasgiven and the changes in heart rate and blood pressure were recordedcontinuously. The main purpose of these experiments was to determine ifthe compounds show any activity at all 60 minutes after administration,considering their very short plasma half-lives. The results shown inFIGURE I indicate that the esters 17 and 13 effectively control theheart rate, although their in vitro plasma half-life is on the order of1 minute. (In vivo hydrolysis rates cannot be measured accurately sincethe drugs were administered i.p. and the in vitro half-life is veryshort.) The extent of this activity is of particular interest, and thetime dependence was determined in the case of 17. Followingadministration of 17, as before, the isoproterenol was administered 15,60 and 90 minutes later and the blood pressure and heart rates wererecorded. It appears from FIG. 2 that at 15 and 60 minutes there issignificant activity on heart rate which, however, disappears at 90minutes. FIG. 3 indicates minimal effect on the blood pressure.

Additional in vivo cardiovascular experiments were performed, usingdogs, which are good models for these types of experiments. In order toavoid the uncertainty due to the intraperitoneal administration used forrats, the active compounds were administered i.v. The changes in heartrate and in left ventricular pressure (LVP) were monitored, as theeffect of isoproterenol was antagonized. Based on the selected leadcompound, the tetramethylcyclohexyl ester 17, the simpler homologues 15and 16 were tested and compared to the simple ethyl ester, 10. All fourcompounds showed 81antagonist activity, but the cyclohexyl ester 15 wasthe most potent in blocking the cardiac effects of isoproterenol. Theother three agents had a comparable ability to blockisoproterenol-induced tachycardia; see FIG. 4.

The time course of the β-adrenergic blockage on heart rate differedamong the four compounds. While 10 produced an antagonism whichdissipated fairly consistently between 45 and 60 minutes afteradministration, the duration of action of 16 and 17 was much morevariable and generally longer. It is interesting to note that just as inrats (FIG. 2, compound 17), in dogs the maximum blockade was not at theearliest time following administration, but at 45 or 60 minutes (TABLEIII). Compound 15 had the longest duration of action; approximately 90minutes were required in most cases for return of heart rateresponsiveness to isoproterenol to the control value (TABLE III).

All compounds shifted the dose-response curve of isoproterenol on leftventricular contractility (dP/dt) to the right. While the extent of thisInotropic blockade may be less than the chronotropic (HR) blockade, theinotropic blockade was more variable. None of the agents were found tohave any significant effect upon the diastolic depressor response toisoproterenol.

Thus, ester type "soft" β-blockers of the present invention based on anacidic inactive metabolite of metoprolol have been show to possesssignificant β-blocking activity. The time of the peak β-blockingactivity and the duration of action do not show any correlation with thein vitro plasma hydrolysis rates. To the contrary, the longest actingcompound, 15, has the shortest plasma hydrolytic half-life (<1 min). Thefast, predictable hydrolytic deactivation of the circulating activespecies must result in reduced overall toxicity and the indirect druginteraction. In view of the structure of known metabolites ofmetoprolol, it is unlikely that oxidative metabolism would compete withthe hydrolysis of the soft derivatives.

EXAMPLE 25

The following illustrates the preparation of an injectable solutioncontaining a representative compound of the invention.

    ______________________________________                                        Ingredient                Amount                                              ______________________________________                                        Cyclohexyl 4-(2-hydroxy-3-isopropylamino)-                                                              500    mg                                           propoxyphenylacetate oxalate 3/4 hydrate                                      Polyethylene glycol       0.3    g                                            (molecular weight 4000)                                                       Sodium chloride           0.9    g                                            Polyoxyethylene sorbitan monooleate                                                                     0.4    g                                            Sodium metabisulfite      0.1    g                                            Methyl paraben            0.18   g                                            Propyl paraben            0.02   g                                            Distilled water for injection                                                                           100    mL                                           ______________________________________                                    

The parabens, sodium metabisulfite and sodium chloride are dissolved indistilled water with stirring at 80° C. The solution is cooled to 40°C., then to this solution are added the compound of the presentInvention, polyethylene glycol and polyoxyethylene sorbitan monooleate,successively. To this solution is added distilled water for injection tothe desired volume, and the solution is then sterilized by filteringthrough a suitable filter paper. One mL portions of this sterilizedsolution are introduced into ampoules.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and additions may be madewithout departing from the spirit thereof. Accordingly, it is intendedthat the scope of the present invention be limited solely by the scopeof the following claims.

What is claimed is:
 1. A compound of the formula ##STR301## or apharmaceutically acceptable acid addition salt thereof, wherein: n isone;R is:--CH₂ --X--R₂ wherein X is S, SO or SO₂ and R₂ is C₁ -C₇ alkylor C₃ -C₁₂ cycloalkyl; ##STR302## wherein R₂ is defined as above; or##STR303## wherein X is defined as above, and wherein R₃ is C₁ -C₇ alkyland R₄ is C₁ -C₇ alkyl, or wherein R₃ and R₄ together represent--(CH₂)_(m) -- wherein m is 3 or 4 and --(CH₂)_(m) -- is optionallysubstituted by one to three C₁ -C₇ alkyl; R₁ is C₁ -C₇ alkyl; and Ar isa divalent fused ring system having two or three rings and at least onebenzene nucleus, and optionally having one or two hetero ring atomsselected from the group consisting of N, O and S.
 2. A compound asdefined by claim 1, wherein R₁ is isopropyl or tert-butyl.
 3. An oxalatesalt of a compound as defined by claim
 1. 4. A compound as defined byclaim 1, wherein R is --CH₂ --X--R₂ wherein X is S, SO or SO₂ and R₂ isC₁ -C₇ alkyl or C₃ -Cl₂ cycloalkyl.
 5. A compound as defined by claim 1,wherein Ar is a radical of the formula ##STR304##
 6. A compound asdefined by claim 1, wherein Ar is a radical of the formula ##STR305## 7.The compound as defined by claim 1, said compound being a compound ofthe formula ##STR306## or a pharmceutically acceptable acid additionsalt thereof.
 8. A method for eliciting a β-adrenergic blocking responsein a warm-blooded animal, which comprises administering to said animalan effective β-adrenergic blocking amount of a compound of formula (I)as defined by claim 1, or a pharmaceutically acceptable acid additionsalt thereof.
 9. A pharmaceutical composition of matter, in unit dosageform, for use in eliciting a β-adrenergic blocking response in awarm-blooded animal, said composition comprising, per dosage unit, aneffective unit β-adrenergic blocking amount of a compound of formula (I)as defined by claim 1 or a pharmaceutically acceptable acid additionsalt thereof, and a non-toxic pharmaceutically acceptable carriertherefor.
 10. A method for the treatment of glaucoma or for loweringintraocular pressure in a warm-blooded animal, which comprisesadministering to the eye or the eyes of said animal an effectiveintraocular pressure decreasing amount of a compound of formula (I) asdefined by claim 1, or a pharmaceutically acceptable acid addition saltthereof.
 11. An ophthalmic composition of matter, in unit dosage form,for use in the treatment of glaucoma or in the lowering of intraocularpressure in a warm-blooded animal, said composition comprising, perdosage unit, an effective unit intraocular pressure decreasing amount ofa compound of formula (I) as defined by claim 1 or a pharmaceuticallyacceptable acid addition salt thereof, and a non-toxic ophthalmicallyacceptable carrier therefor.